Doi:10.1016/j.ejpain.2005.03.004

European Journal of Pain 10 (2006) 185–192
Guidelines for the use of antidepressants in painful
Serge Perrot *, Emmanuel Maheu, Rose-Marie Javier, Alain Eschalier, Anne Coutaux,
Manuela LeBars, Philippe Bertin, Bernard Bannwarth, Richard Tre`ves
Cercle dÕe´tude de la douleur en rhumatologie, CEDR, Limoges, France
Received 31 August 2004; accepted 11 March 2005
Objectives: Antidepressants are widely used to treat painful chronic rheumatic conditions but, contrary to neuropathic conditions,
little is known about their true analgesic properties and value in these situations. Our group, which focuses on pain in rheumatology,aimed to develop recommendations for the use of antidepressants in rheumatology, based on evidence-based review of publisheddata and expert opinion.
Method: We identiﬁed relevant drugs and conditions and searched Medline, Embase and Pascal (1966–2003) for relevant publica-
tions in a number of European languages. We scored each study for quality, and used an expert consensus approach to formulaterecommendations.
Results: We identiﬁed 77 studies and 12 meta-analyses and literature review on the use of antidepressant to treat painful rheuma-
tological conditions. Forty-nine of these clinical studies were considered valid and were used to develop the recommendations. Whenevidence was lacking we based recommendations on our clinical experience.
Conclusions: These recommendations for the treatment of painful rheumatological conditions with antidepressants were devel-
oped using evidence-based and expert consensus approaches and are the ﬁrst of their kind in this ﬁeld. Our review of the literaturehighlights the need for further, well-designed clinical studies of the use of antidepressants to treat painful rheumatologicalconditions.Ó 2005 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. Allrights reserved.
Keywords: Pain; Musculoskeletal; Antidepressants; Treatment; Recommendations
eﬀectively. However, in some cases, additional treat-ments, such as antidepressants and anticonvulsants,
Pain is the main symptom of many rheumatic condi-
diseases. In many cases, analgesics, non steroidal anti-
inﬂammatory drugs (NSAIDs) or opioids control pain
is increasingfor many conditions, including ﬁbromyalgia, rheuma-toid arthritis, spondylarthropathies, low back pain and
* Corresponding author. Address: centre de la Douleur, hoˆpital
osteoarthritis. Although antidepressants have often been
Cochin-Tarnier, 89 Rue dÕAssas, 75006 Paris, France. Tel.: +33 1 58 41
shown to reduce pain, the results obtained are variable
1090-3801/$32 Ó 2005 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rightsreserved.doi:10.1016/j.ejpain.2005.03.004
S. Perrot et al. / European Journal of Pain 10 (2006) 185–192
All potentially relevant papers were retrieved and
For example: Does the analgesic eﬀect depend
their ﬁndings were analyzed by all members. The list
on the antidepressant eﬀect? What is the optimal dose?
of clinical questions used to deﬁne the scope of the liter-
When is such treatment appropriate? How long should
ature search was also used to structure the recommenda-
tions together with another set of guidelines (on the use
Guidelines are therefore required concerning the use
of opioids for the treatment of chronic pain) which had
of these drugs. This document reviews the available evi-
been developed by a similar expert group, including one
dence and then proposes a framework for the develop-
ment of guidelines, without providing detailed advice
rate sections were drafted by various participants using
about doses or formulations. It is designed to be a start-
the evidence from the literature review wherever
ing point for discussion and to be suﬃciently ﬂexible to
gain practical acceptance in diﬀerent countries. It aims
The draft recommendations were circulated among
to help prescribers (in primary care or specialist settings)
the authors for further review and critical evaluation.
to use antidepressants appropriately for the manage-
A Delphi approach was then employed to reach con-
ment of pain in rheumatic conditions.
sensus and all the recommendations were collated andsent back to the experts, who were asked to rank the10 most important proposals. A ﬁnal draft of the rec-ommendations was generated, taking into account the
comments and criticisms of the nine panel members.The Delphi method is an exercise in group communi-
cation among a panel of geographically dispersed ex-perts. It enables experts to deal systematically with a
This study was carried out by a working group of
complex problem or task. The essence of the tech-
nine experts for the CEDR (Cercle dÕEtude de la Doul-
nique is fairly straightforward. It comprises a series
eur en Rhumatologie) a speciﬁc interest group of the
of questionnaires sent by post or e-mail to a pre-
French Society of Rheumatology that focuses on rheu-
selected group of experts. These questionnaires are de-
matic pain. Seven of the experts involved in this study
signed to elicit and to develop individual responses to
were rheumatologists, one of whom was also a pharma-
the problems posed and to enable the experts to reﬁne
cologist. The other members were a psychiatrist and a
their views as the groupÕs work progresses in accor-
dance with the assigned task. The Delphi methodmakes it possible to overcome the disadvantages of
conventional committee action. The group interactionin Delphi is anonymous, in that the originator of
Relevant treatments and conditions were identiﬁed
comments, forecasts, and the like is not identiﬁed.
by the panel. We then searched the Medline, Embase
These elements are presented to the group in such a
and Pascal databases for publications in several Euro-
way as to suppress any identiﬁcation. Here are the
pean languages. Search terms used were: antidepressant,
pain, rheumatoid arthritis, osteoarthritis, low back pain,ﬁbromyalgia, ﬁbrositis, rheumatic diseases, spond-
1. Formation of a team to undertake and to monitor
ylarthropathy, ankylosing spondylarthritis, and sympa-
thetic dystrophy. The search period covered 1966 to
2. Selection of one or more panels to participate in
August 2002. Studies were scored using the EULAR
the exercise. Panel members are usually experts
on a checklist. This checklist consists of 27 items distrib-
uted between ﬁve sub-scales and was developed on the
basis of epidemiological principles, reviews of study
4. Testing the questionnaire for proper wording (e.g.,
designs, and existing checklists for the assessment of
5. Transmission of the ﬁrst questionnaires to the
checklist provides a quality assessment of the reporting,
external and internal validity and statistical power of
6. Analysis of the ﬁrst-round responses.
each study. All studies are scored 0–1 for 26 questions
7. Preparation of the second-round questionnaires
and 0–2 for one question, giving a maximum score of
28. Power calculations are scored as 1 if present and 0
8. Transmission of the second-round questionnaires
S. Perrot et al. / European Journal of Pain 10 (2006) 185–192
9. Analysis of the second-round responses (steps 7–9
pram were found to have a positive eﬀect on neuro-
are reiterated as long as many times as required to
pathic pain. Venlafaxine was recently shown to reduce
neuropathic pain following chemotherapy for breast
10. Preparation of a report by the analysis team to
present the conclusions of the exercise.
ﬁbromyalgic patients (). But, exceptin neuropathic conditions and in ﬁbromyalgia, there is
The recommendations were then tested according the
no convincing study that really aimed to compare TCAs
with SSRIs or other new antidepressants in speciﬁc
independent reviewers and the strength of the evidence
chronic pain states and speciﬁcally rheumatological.
supporting each recommendation was indicated, from
For most of the authors antidepressant analgesic eﬀects
are independent of their eﬀects on mood (
praisal of Guidelines Research & Evaluation (AGREE)Instrument is to provide a framework for assessing the
3.2. Evaluation of the dose–response eﬀect in chronic pain
quality of clinical practice guidelines. The AGREEInstrument is designed to assess guidelines developed
There is no clear evidence for a dose-dependent re-
by local, regional, national or international groups.
sponse to antidepressant treatment in terms of pain re-
The AGREE Instrument is generic and can be applied
to guidelines in any disease area. The AGREE Instru-
studies that dealt speciﬁcally with rheumatic pain. Con-
ment assesses both the quality of the reporting, and
ﬂicting data have been obtained concerning the possible
the quality of some aspects of recommendations. It pro-
relationship between concentration and analgesic eﬀect,
vides an assessment of the predicted validity of a guide-
but current therapeutic plasma concentration ranges
line, the likelihood that it will achieve its intended
seem to give an acceptable response for TCAs. Several
outcome. It does not assess the impact of a guideline
studies in which TCAs were administered for various
types of neuropathic pain reported a relationship be-tween serum drug concentration and analgesic eﬀect(For the
newer antidepressants, also in neuropathic pain, somestudies suggested that plasma concentration and eﬀect
We identiﬁed 137 relevant papers and, of these, se-
are correlated (e.g. for sertraline and paroxetine for neu-
lected 99 for detailed analysis: 77 were randomised con-
ropathic pain) and others reported no such correlation
trolled studies and 12 were meta-analyses or literature
(e.g. for ﬂuoxetine and citalopram for neuropathic pain)
review. The results are summarised below.
3.1. Global review of analgesic eﬀects of antidepressants
3.1.1. Analgesic eﬀect of antidepressants
The analgesic response seems to start before the anti-
Analysis of 39 studies in various chronic naon-malig-
depressant response. An analgesic response is usually
observed within one week of starting treatment, whereas
found that antidepressants had an analgesic
the antidepressant response usually occurs after the ﬁrst
eﬀect, conﬁrmed by Lynch in a meta-analysis of 59 stud-
ies (In neuropathic pain, the results are
convincing and have demonstrated diﬀerential analgesiceﬀects regarding the group of the drug:
3.4. Evaluation of diﬀerent routes and patterns of
were more eﬀective than serotonin-speciﬁc reuptakeinhibitors (SSRIs) in relieving neuropathic pain. In
The advantages of the various routes of administra-
global assessment of eﬀects of antidepressants in chronic
tion are unclear in humans. Due to a marked ﬁrst-pass
pain states, most of the authors have concluded that the
eﬀect, oral bioavailability ranges from 20 to 80% (see
tricyclic group of antidepressants is analgesic and that
data regarding selective serotonin reuptake inhibitors
morphism may also play a role in the pronounced phar-
are conﬂicting (). A review of the use of
macokinetic variability observed with these drugs.
antidepressants in pain management, including rheu-
Parenteral administration overcomes the problem of
ﬁrst-pass metabolism, and results in high plasma con-
replace TCAs by SSRIs in pain management. In a other
centrations. However, apart from a possible indication
review comparing some of the newer antidepressants
in patients unable to swallow, the parenteral route seems
to have no other real advantage, despite reports that this
S. Perrot et al. / European Journal of Pain 10 (2006) 185–192
route may accelerate the onset of the therapeutic eﬀect
identiﬁed in ﬁbromyalgia studies, and antidepressantshave not been shown to have a lasting eﬀect.
Amitriptyline is the most widely used drug for which
an eﬀect on pain, fatigue, sleep and general conditions
Imipraminic drugs, and TCAs in particular, cause side
eﬀect in 30–100% of patients treated for painful condi-
have a greater eﬀect on sleep disorders and fatigue than
eﬀects are more frequent in ﬁbromyalgia, occurring in
ported the use of tricyclic drugs at doses lower than
Side eﬀects parallel TCAs analgesic eﬀects and,
those used to treat depression, probably due to the side
pid wash-out may lead to severe symptoms, such as nau-
Recent studies have assessed the eﬀects of newer anti-
Before starting TCA treatments, the physician should
check for orthostatic hypotension and perform an
ECG. No recommendations have yet been published
with a view to preventing the side eﬀects of TCAs. The
eﬀects of combined treatment with tramadol should also
these cases, the doses used were higher than or similar
quent co-utilization in rheumatological conditions.
studies have been carried out on the newer antidepres-
SSRIs have been demonstrated to be well tolerated
sants and the available studies had low quality scores
and safe. The only reported side eﬀects are abdominal
in many cases. However it seems that although these
symptoms at the start of the treatment, and serotoniner-
drugs are better tolerated than tricyclic drugs at high
gic syndrome. Side eﬀects are reported in up to 80% of
patients treated for painful conditions (
Overall, TCAs appear to be the most eﬀective antide-
pressants for the management of pain and other symp-
but are clinically relevant in a lower proportion (0–
toms in ﬁbromyalgia, even if a large placebo eﬀect was
rate of treatment drop-outs with SSRIs than with TCAs
SSRIs are better tolerated but less eﬀective, making it
are well tolerated, about as well as placebo (
necessary to increase the dose to obtain signiﬁcant pain
and are therefore more readily prescribed. Furthermore,no tests are required before starting SSRI treatment.
Combination with tramadol is also not recommended.
Seven randomised, controlled trials of good quality
have been published on this topic. Four reviews have
3.6. Use of antidepressants in patients with speciﬁc
precisely examined the analgesic and functional eﬀects
We identiﬁed 47 studies on the use of antidepressants
clinical papers was 11 (range: 6–15). Analysis of these
in ﬁbromyalgia, including 25 controlled trials, most of
studies suggested that antidepressants were slightly more
which involved tricyclic agents; and there were three
eﬀective than placebo for the relief of low back pain.
Antidepressant treatment also tended to improve func-
tion and everyday activities, although this trend was
quality scores for these papers was 14.5 (range: 8–24).
Despite their widespread use, tricyclic drugs have
). One study indicated that imipramine was
only a moderate eﬀect and only a minority of patients
more eﬀective than placebo, but only in terms of the
‘‘numbers of days had to lie down’’ and ‘‘number of
days with at least some restriction of normal activity’’
showed that amitryptyline was better than pla-
cebo, comparing the use of rescue analgesics in both
treatment groups. Nortriptyline and maprotiline were
S. Perrot et al. / European Journal of Pain 10 (2006) 185–192
signiﬁcantly more eﬀective than placebo, but nonethe-
published guidelines on the treatment of chronic pain
less had only moderate analgesic eﬀects (
concerning the use of antidepressants in painful rheu-
). In conclusion, tricyclic and tetracyclic antidepres-
matic conditions. The strength of the evidence support-
sants appear to produce moderate symptom reductions
ing each recommendation is indicated, from A to D
for patients with chronic low back pain, independently
of a patientÕs depression status. Selective serotonin reup-take inhibitors (SSRIs) do not appear to be beneﬁcial.
1. Due to their analgesic and antidepressant proper-
The eﬀect of antidepressants on health-related quality
ties, antidepressants can improve the symptoms
of life, mood and functional status is unclear (
and quality of life of patients suﬀering from pain-
ful chronic degenerative and inﬂammatory osteo-articular and spinal diseases. Their use should be
3.6.3. Osteoarthritis and inﬂammatory rheumatic diseases
included in a global management programme
We identiﬁed 15 randomised controlled trials on
together with non-pharmacological approaches. A
osteoarthritis (OA), rheumatoid arthritis (RA), and
2. Antidepressants, especially tricyclic drugs, are rec-
ankylosing spondylitis (AS). Fourteen of these studies
ommended as analgesics for ﬁbromyalgia. They
were placebo-controlled and one compared amitrypti-
should not be ﬁrst choice analgesic treatment in
line with paroxetine. Only eight of these 15 trials were
low back pain, osteoarthritis and inﬂammatory
considered to meet the minimum standards in terms
of methodological quality to demonstrate eﬃcacy (
3. To increase compliance, patients prescribed anti-
depressants for analgesic use should be informed
of the type of drug, its side eﬀects, the aim of the
treatment and the expected delay until the analge-
studies scored from 13 to 22 on a scale with a maximum
of 28 (median quality score: 16.4). In almost all these tri-
4. Antidepressants may be prescribed as analgesics in
als, eﬃcacy in the control of pain and symptoms was
non-depressed patients. The ﬁrst-choice treatment
independent of the antidepressant eﬀect (with the excep-
should be a TCA, initiated at a low dose, which
is then increased to the maximal tolerated dose
which included depressed patients). Thus, ami-
tryptyline, trimipramine, dothiepine and paroxetine
5. Newer antidepressants with mixed action or spe-
may have analgesic eﬀects in patients with RA, and ami-
ciﬁc serotonin reuptake inhibitors should be tried
tryptiline may be eﬀective in reducing symptoms in AS.
only if TCAs prove to be ineﬀective, poorly toler-
Analgesic eﬀects of antidepressant were usually detected
ated or if they are contraindicated. Another anti-
after one week of treatment. Low doses of amitryptiline
depressant (from the same class or another class)
(10–30 mg daily) may be suﬃcient to provide an analge-
can be tried after failure of the initial antidepres-
sant treatment, regardless of whether this failure
is related to a lack of eﬃcacy or unbearable side
None of the studies speciﬁcally dealt with OA; it is
therefore diﬃcult to determine whether antidepressants
6. The side eﬀects of antidepressants used as analge-
are beneﬁcial for this condition. Some studies grouped
sics are similar to those observed in the treatment
together patients with OA, RA and AS, and reported
of depression. They may be treated from treatment
a small, but signiﬁcant analgesic eﬀect with TCAs and
initiation and throughout the treatment period. A
7. If TCAs are prescribed to elderly patients, the phy-
sician should monitor blood pressure, cognition
and diverse population of older adults with arthritis
8. The assessment of treatment eﬃcacy should not be
(mostly osteoarthritis) and comorbid depression, bene-
limited to pain evaluation. It should include func-
ﬁts of improved depression care extended beyond re-
tional evaluation, analgesic consumption, sleep
duced depressive symptoms and included decreased
(quality and duration) evaluation, and psycho-
pain as well as improved functional status and quality
sociological assessment, and should be started
9. There is no optimal duration of antidepressant
3.7. General guidelines for the use of antidepressants
treatment. Antidepressant treatment should bemaintained for at least 4 weeks before being
Based on the ﬁndings of the 75 studies analyzed, the
stopped due to lack of eﬃcacy. Total duration
clinical experience of the expert panel, and previously
should be determined with respect to the initial
S. Perrot et al. / European Journal of Pain 10 (2006) 185–192
objectives, accepted by both the patients and the
of antidepressants. Some clinicians have reported suc-
physician, and after careful risk-beneﬁt evaluation.
cessful treatment with SSRIs following the failure of tri-
cyclics drugs, however no clinical studies have been
10. After 3 to 6 months of remission, the dose may be
performed in this area. Further studies are needed to
gradually decreased, with regular pain assess-
investigate the role of plasma concentration, the inﬂu-
ments. Stopping the treatment too abruptly may
ence of concomitant psychiatric disturbances, and the
lead to nausea, vomiting and trembling. B
type of organic lesions on the analgesic response to anti-depressant eﬀects. Another ﬁeld for future research is
A = based on category 1 evidence; B = based on cat-
the possibility of co-administering drugs to increase
egory 2 evidence or extrapolated recommendation from
the eﬃcacy of antidepressants or to reduce their adverse
category 1 evidence; C = based on category 3 evidence
eﬀects. Following the development of clinical guidelines
or extrapolated recommendation from category 1 or 2
evidence; D: based on category 4 evidence or extrapo-
vise these recommendations in a next future, to keep it
relevant, according to most recent clinical ﬁndings,
and mostly to both the patientÕs and physicianÕsexperience.
Guidelines should be based on available evidence and
this was the goal of this expert group. However, we soon
The AGREE Collaboration. AGREE instrument,
realised that little or no evidence was available for many
of the key issues, because of the paucity of appropriate
Alcoﬀ J, Jones E, Rust P, Newman R. Controlled trial of imipramine
for chronic low back pain. J Fam Pract 1982;28:841–6.
clinical studies and as clinical studies does not reﬂect
Andenberg UA, Marteinsdottir I, von Knorring L. Citalopram in
the real clinical situations, e.g. and long-term utilization
patients with ﬁbromyalgia – a randomised, double-blind, placebo-
in painful chronic situations. The published studies pro-
controlled study. Eur J Pain 2000;4:27–35.
vide little information useful to determine which individ-
Ansari A. The eﬃcacy of newer antidepressants in the treatment of
uals respond to antidepressants with analgesic eﬀects.
chronic pain: a review of current literature. Harvard Rev Psychi-atry 2000;7(5):257–77.
More studies have focused on ﬁbromyalgia than on
Arnold LM, Keck PE, Welge JA. Antidepressant treatment of
other conditions, but although there is a trend towards
the use antidepressants in ﬁbromyalgia, no clear analge-
sic eﬀects have been demonstrated in this situation. The
Arnold LM, Hess EV, Hudson JI, Welge JA, Berno SE, Keck Jr PE. A
results of studies on osteoarthritis, low back pain and
randomized, placebo-controlled, double-blind, ﬂexible-dose studyof ﬂuoxetine in the treatment of women with ﬁbromyalgia. Am J
rheumatoid arthritis are not very convincing. There
has also been no comparative study of patients with dif-
Ash G, Dickens CM, Creed FH, Jayson MI, Tomenson B. The eﬀects
ferent, speciﬁc rheumatological conditions. It is also not
of dothiepin on subjects with rheumatoid arthritis and depression.
yet possible to determine which type of pain will respond
Rheumatology (Oxford) 1999;38:959–67.
most strongly to treatment with antidepressants. Fur-
Ataoglu S, Ataoglu A, Erdoan F, Sarac¸ J. Comparison of paroxetine,
amitriptyline in the treatment of ﬁbromyalgia. Turk J Med Sci
thermore, it is not possible to deﬁne predictive factors
for analgesic eﬀects: psychological status does not pre-
Atkinson JH, Slater MA, Williams RA, Zisook S, Patterson TL, Grant
dict analgesic eﬀect and antidepressants do not exhibit
I, et al. A placebo-controlled randomised clinical trial of nortrip-
more powerful analgesic eﬀects in depressed patients.
tyline for chronic low back pain. Pain 1998;76:287–96.
These recommendations have been tested by two
Atkinson JH, Slater MA, Wahlgreen DR, Williams RA, Zisook S,
Pruitt, et al. Eﬀects of noradrenergic and serotoninergic antide-
independent reviewers, according the AGREE method
pressants on chronic low back pain. Pain 1999;83:137–45.
Barkin RR, Fawcett J. The management challenges of chronic pain:
for the assessment of clinical guidelines. Global
the role of antidepressants. Am J Therapeut 2000;7:31–47.
assessment was good, and speciﬁc assessments of each
Bennett RR, Gatter RR, Campbell SS, Andrews RR, Clark SS,
the 6 domains were rated with scores ranging from
Scarola JA. A comparison of cyclobenzaprine and placebo in themanagement of ﬁbrositis. A double-blind controlled study. Arthri-
53% to 100%, thus allowing the spreading of these
Bibolotti E, Borghi C, Pasculli E, Regoli F, Tavoni A, Baroni L, et al.
These recommendations also gave us the opportunity
The management of ﬁbrositis. A double-blind comparison of
to deﬁne research guidelines. The responsiveness of
maprotiline (Ludiomil) clorimipramine and placebo. Clin Trials J
many chronic pain conditions, especially rheumatologi-
Bird H, Broggini M. Paroxetine versus amitriptyline for treatment of
cal, to antidepressants has not been assessed in
controlled settings and we know very little about the
ized, double blind, parallel group study. J Rheumatol 2000;27:
long-term (months to years) eﬃcacy and adverse eﬀects
S. Perrot et al. / European Journal of Pain 10 (2006) 185–192
Blier P, Abbott FV. Putative mechanisms of action of antidepressant
Gringras M. A clinical trial of tofranil in rheumatic pain in general
drugs in aﬀective and anxiety disorders and pain. J Psychiatry
practice. J Int Med Res 1976;4(Suppl 2):41–9.
Hamaty D, Valentine JL, Howard R, Howard CW, Wakeﬁeld V, Patten
Bryson HH, Wilde MM. Amitriptyline. A review of its pharmacolog-
MS. The plasma endorphin, prostaglandin and catecholamine
ical properties and therapeutic use in chronic pain states. Drugs
proﬁle of patients with ﬁbrositis treated with cyclobenzaprine and
placebo: a 5-month study. J Rheumatol Suppl 1989;19:164–8.
Cantini F, Bellandi F, Niccoli L, Di Munno O. Fluoxetina associata a
Hannonen P, Malminiemi K, Yli-Kerttula U, Isomeri R, Roponen P.
ciclobenzaprina nel trattamento della ﬁbromialgia. Minerva Med
A randomized, double-blind, placebo-controlled study of moclobe-
mide and amitriptyline in the treatment of ﬁbromyalgia in females
Carette S, McCain GG, Bell DD, Fam AA. Evaluation of amitrip-
without psychiatric disorder. Br J Rheumatol 1998;37:1279–86.
tyline in primary ﬁbrositis. A double-blinded, placebo-controlled
Heymann RE, Helfenstein M, Feldman D. A double-blind, random-
study. Arthritis Rheum 1986;29:655–9.
ised, controlled study of amitriptyline, nortriptyline and placebo in
Carette S, Bell MM, John Reynolds W, Haraqui B, McCain GG,
patients with ﬁbromyalgia. An analysis of outcome measures. Clin
Bykerk VV, et al. Comparison of amitriptyline, cyclobenzaprine,
and placebo in the treatment of ﬁbromyalgia. Arthritis Rheum
Hood SD, Argyropoulos SV, Nutt DJ. Arthritis and serotoninergic
antidepressants. J Clin Psychopharmacol 2001;24:458–61.
Caruso I, Sarzi Puttini PC, Boccassini L, Santandrea S, Locati M,
Jaeschke R, Adachi J, Guyatt G, Keller J, Wong B. Clinical usefulness
Volpato R, et al. Double-blind study of dothiepin versus placebo
of amitriptyline in ﬁbromyalgia:the results of 23 N-of-1 random-
in the treatment of primary ﬁbromyalgia syndrome. J Int Med Res
ized controlled trials. J Rheumatol 1991;18:447–51.
Jenkins DG, Ebbutt AF, Evans CD. Tofranil in the treatment of low
Cortet B, Houvenagel E, Forzy G, Vincent G, Delcambre B.
back pain. J Int Med Res 1976;4:28–40.
Evaluation de lÕeﬃcacite´ dÕun traitement se´rotoninergique (chlor-
Jung AA, Staiger T, Sullivan M. The eﬃcacy of selective serotonin
hydrate de ﬂuoxetine). Etude ouverte au cours de la ﬁbromyalgie.
reuptake inhibitors for the management of chronic pain. J Gen
Rev Rhum Mal Osteoartic 1992;59:497–500.
Curatolo M, Bogduk N. Pharmacologic pain treatment of musculo-
Kalso E, Allan L, Dellemijn PL, Faura CC, Ilias WK, Jensen TS,
skeletal disorders:current perspectives and future prospects. Clin J
et al. Recommendations for using opioids in chronic non-cancer
Dickens C, Jayson M, Sutton C, Creed F. The relationship between
Koh WW, Pande I, Samuels A, Jones SS, Calin A. Low dose
pain and depression in a trial using paroxetine in suﬀerers of
amitriptyline in ankylosing spondylitis: a short term, double blind,
chronic low back pain. Psychosomatics 2000;41:490–9.
placebo controlled study. J Rheumatol 1997;4:2158–21561.
Dwight MM, Arnold LL, OÕBrien H, Metzger R, Morris-Park E, Keck
Lawson K. Tricyclic antidepressants and ﬁbromyalgia: what is the
PP. An open trial of venlafaxine treatment of ﬁbromyalgia.
mechanism of action?. Expert Opin Invest Drugs 2002;11: 1437–45.
Lin EH, Katon W, Von Korﬀ M, Tang L, Williams Jr JW, Kroenke K,
Egbunike IG, Chaﬀe BJ. Antidepressants in the management of
et al. Eﬀect of improving depression care on pain and functional
chronic syndromes. Pharmacotherapy 1990;10:262–70.
outcomes among older adults with arthritis: a randomized
Eschalier A, Ardid D Dubray C. Tricyclic and other antidepressants as
controlled trial. JAMA 2003;290:2428–9.
analgesics. In: Jana, editor. Novel aspects of pain management:opi-
Lynch EE. Antidepressants as analgesics: a review of randomised
controlled trials. J Psych Neurosci 2001;26:30–6.
Fossaluzza V, De Vita S. Combined therapy with cyclobenzaprine and
Macfarlane JG, Jalali S, Grace EM. Trimipramine in rheumatoid
ibuprofen in primary ﬁbromyalgia syndrome. Int J Clin Pharm Res
arthritis: a randomized double-blind trial in relieving pain and joint
tenderness. Curr Med Res Opin 1986;10(2):89–93.
Fowler PD, MacNeill A, Spencer D, Robinson ET, Dick WC.
MacNeill AL, Dick WC. Imipramine and rheumatoid factor. J Int
Imipramine, rheumatoid arthritis and rheumatoid factor. Curr
Magni G. The use of antidepressants in the treatment of chronic pain.
Frank RG, Kashani JH, Parker JC, Beck NC, Brownlee-Duﬀeck M,
Elliott TR, et al. Antidepressant analgesia in rheumatoid arthritis.
McDonald Scott WA. The relief of pain with an antidepressant in
arthritis. Practitioner 1969;202:802–7.
Furlanut M, Benetello P, Spina E. Pharmacokinetic optimisation of
McQuay HJ, Carroll D, Glynn CJ. Low-dose amitriptyline in the
treatment of chronic pain. Anesthesia 1992;47:646–52.
McQuay HJ, Carroll D, Glynn CJ. Dose–response for analgesic eﬀect
Ganvir P, Beaumont G, Seldrup J. A comparative trial of clomipra-
of amitriptyline in chronic pain. Anaesthesia 1993;48:281–5.
mine and placebo as adjunctive therapy in arthralgia. J Int Med
McQuay HJ, Trame`r M, Nye BA, Carroll D, Wiﬀen PJ, Moore RA. A
systematic review of antidepressants in neuropathic pain. Pain
Geller SS. Treatment of ﬁbrositis with ﬂuoxetine hydrochlorhyde
(ProzacÒ). Am J Med 1989;87:594–5.
Norregard J, Volkmann H, Danneskiold-Samsoe B. A randomized
controlled study of citalopram in the treatment of ﬁbromyalgia.
controlled trial of amitriptyline and naproxene in the treat-
ment of patients with ﬁbromyalgia. Arthritis Rheum 1986;29:
OÕMalley PP, Balden E, Tornkins G, Santoro J, Kroenke K, Jackson
JJ. Treatment of ﬁbromyalgia with antidepressants. A meta-
Goldenberg D, Mayskiy M, Mossey C, Ruthaser R, Schmid C. A
randomized, double-blind crossover trial of ﬂuoxetine and ami-
Olin R, Klein R, Berg PA. A randomised double-blind 16-week study
triptyline in the treatment of ﬁbromyalgia. Arthritis Rheum
of ritanserin in ﬁbromyalgia syndrome: clinical outcome and
analysis of autoantibodies to serotonin, gangliosides and phospho-
Grace EM, Bellamy N, Kassam Y, Buchanan WW. Controlled,
lipids. Clin Rheumatol 1998;17:89–94.
double-blind, randomized trial of amitriptyline in relieving artic-
Onghena P, Van Houdenhove B. Antidepressant-induced analgesia in
ular pain and tenderness in patients with rheumatoid arthritis. Curr
chronic non-malignant pain: a meta-analysis of39 placebo-con-
S. Perrot et al. / European Journal of Pain 10 (2006) 185–192
Parker JC, Smarr KL, Slaughter JR, Johnston SK, Priesmeyer ML,
Sindrup SS, Grodum E, Gram LL, Beck-Nielsen H. Concentration
Hanson KD, et al. Management of depression in rheumatoid
response relationship of paroxetine treatment in diabetic neurop-
arthritis: a combined pharmacologic and cognitive-behavioral
athy. A patient-blinded dose escalation study. J Monit 1991;13:
approach. Arthritis Rheum 2003;49:766–77.
Pendleton A, Arden N, Dougados M, Doherty M, Bannwarth B, et al.
Sindrup SS, Brosen K, Gram LL. Antidepressant in pain treatment:
EULAR recommendations for the management of knee osteoar-
antidepressant or analgesic eﬀect?. Clin Neuropharm 1992;15:
thritis: report of a task force of the Standing Committee for
International Clinical Studies Including Therapeutic Trials (ESCI-
Sindrup SH, Jensen TS. Eﬃcacy of pharmacological treatments of
SIT). Ann Rheum Dis 2000;59:936–44.
neuropathic pain: an update and eﬀect related to mechanism of
Pheasant H, Bursk A, Godfarb J, Azen SS, Weiss JJ, Borelli L.
drug action. Pain 1999;83:389–400.
Amitriptyline and chronic low back pain. Spine 1983;8:552–7.
Smith AA. The analgesic eﬀects of selective serotonin reuptake
Phillip M, Fickinger M. Psychotropic drugs in the management of
inhibitors. J Psychopharmacol 1998;12:407–13.
chronic pain syndromes. Pharmacopsychiatry 1993;26:221–34.
Staiger TO, Gaster B, Sullivan MD, Deyo RA. Systematic review of
Pollock BG, Perel JM, Shostac M, Antelman SM, Brandon B, Kupfer
antidepressants in the treatment of chronic low back pain. Spine
DJ. Understanding the response lag to tricycles: application of
pulse loading regimens with intravenous clomipramine. Psycho-
Tasmuth T, Hartel B, Kalso E. Venlafaxine in neuropathic pain
following treatment of breast cancer. Eur J Pain 2002;6:17–24.
Quimby LG, Gratwick GM, Whitney CD, Block SR. A randomized
Thorpe P, Marchant-Williams R. The role of an antidepressant,
trial of cyclobenzaprine for the treatment of ﬁbromyalgia. J
dibenzepin (Noveril), in the relief of pain in chronic arthritic states.
Reus VV, Rawitscher L. Possible interaction of tramadol and
Tre`ves R, Montane De La Roque Ph, Dumond JJ, Bertin Ph, Arnaud
antidepressants. Am J Psychiatry 2000;157:839.
M, Desproges-Gotteron R. Etude prospective de lÕaction antalgi-
Reynolds WJ, Moldofsky H, Saskin P, Lue FA. The eﬀects of
que de la clomipramine versus placebo dans les lombosciatalgies
cyclobenzaprine on sleep physiology and symptoms in patients
rebelles(68 cas). Rev Rhum 1991;58:549–52.
with ﬁbromyalgia. J Rheumatol 1991;18:452–4.
Turner JA, Denny MC. Do antidepressant agents relieve chronic low
Salerno SM, Browning R, Jackson JL. The eﬀect of antidepressant
back pain?. J Fam Pract 1993;37:545–53.
treatment on chronic back pain. Arch Intern Med 2002;162:19–24.
Usha Rani P, Naidu MUR, Prasad VBN, Ramesh Kumar Rao T,
Sarzi Puttini P, Cazzola M, Boccassini L, Ciniselli G, Santandrea S,
Shobha JJ. An evaluation of antidepressants in rheumatic pain
Caruso I, et al. A comparison of dothiepin versus placebo in the
conditions. Anesth Analg 1996;83:371–5.
treatment of pain in rheumatoid arthritis and the association of
van Tulder MW, Koes BW, Bouter LM. Conservative treatment of
pain with depression. J Int Med Res 1988;16:331–7.
Sawynok J, Esser MM, Reid AR. Antidepresssants as analgesics: an
overview of central and peripheral mechanisms of action. J
Ward NN. Tricyclic antidepressants for chronic low back pain. Spine
Psychiatry Neurosci 2001;26(1):21–9.
Sayar K, Aksu G, Ak I, Tosun M. Venlafaxine treatment of
Watson C, Peter N. Antidepressant drugs as adjuvant analgesics. J
ﬁbromyalgia. Ann Pharmacother 2003;37:1561–5.
Pain Symptom Manage 1994;9:392–405.
Scudds RA, McCain GA, Rollman GB, Harth M. Improvements in
White KP, Harth M. An analytical review of 24 controlled clinical
pain responsiveness in patients with ﬁbrositis after successful
trials of ﬁbromyalgia syndrome (FMS). Pain 1996;64:211–9.
treatment with amitriptyline. J Rheumatol Suppl 1989;19:98–103.
Wolfe F, Cathey MM, Hawley DJ. A double-blind placebo controlled
Shekelle PG, Woolf SH, Eccles M, Grimshaw J. Clinical guidelines:
developing guidelines. BMJ 1999;318:593–6.
Simms RW, Felson DT, Goldenberg DL. Development of preliminary
Zitman FF, Linsse ACG, Edelbroek PM, VanKempen GG. Clinical
criteria for response to treatment in ﬁbromyalgia syndrome. J
eﬀectiveness of antidepressants and antipsychotics in chronic
benign pain. Clin Neuropharm 1992;15(S1):377A.

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